Unsaturated morphinan derivatives



United States Patent ice ente peff zfi al as anti-tussive, analgesic, narcotic, anti-extensor and/0r 3,236,851 anti-electroshock-convulsant activity. UNSATURATED MORPHINAN DERIVATIVES Accordingly, a basic objectof the present invention is Yoshi, s and i Maeda, HyOgO p f t Japan, to embody the unsaturated morphinans derivative of Forassignors to Shionogi & Co., Ltd., Osaka, Japan 5 mula I. Another object of the invention is to embody No Drawing. Filed Apr. 3, 1963, Ser. No. 270,185 the pharamacologically active unsaturated morphinans Claims P y, l lgg l g g p P 1962, (I). A further object of the invention is to embody a process for preparing .the unsaturated morphinans (I).

o Chums (CL 260-285) These and other objects will be apparent to those conver- 0 sant with the art to which the present invention pertains 1 The present invention relates to unsaturated morphinan from the subsequent descrlption.

derivatives and production thereof. The process of the present invention is illustratively In the term morphinan herein employed, there are represented by the following scheme:

M2" N-R" nil 11' '8020 (III) (D included all the compounds having a fundamental strucwherein R, R, R", X each has the same significance as ture representable -by the following plane formula: designated above and there is a double bond in ring-C 2 and R' represents a lower alkyl group (e.g. methyl, 3 ethyl, propyl), an aryl group (e.g. phenyl, tolyl, xylyl) or an ar(lower)alkyl group (e.g. benzyl, phenethyl).

4 10 As the starting material, there may be used the optically active or racemic hydroxymorphinan of Formula II. 5 According to the process of the present invention, the 4 NH starting hydroxymorphinan (II) is subjected to sulfonyla- 6 8 tion, followed by deacidation of the resultant sulfonyloxy- 7 morphinan of Formula 111 to give the objective unsatudi l h term morphinan means not only Hop rated morphinan (I). The sulfonylation is accomplished rnal morphinan (cis-l,3,4,9,10,10a-hexahyd-ro-2H-10,4a-' y treating the hydroxymorphinan with a sulfonyl iminoethanophenanthrene) but also isomorphinan (transhalide -gbelllefleslllfonyl chloride, benlellesulfonyl 1,3,4,9,10,10a hexahydro-ZH-10,4a-iminoethanophenan- O bromide, toluenesulfonyl chloride, toluenesulfonyl brothrene), inclusively. When distinction is necessary, nor mide, methanesulfony-l chloride, ethanesulfonyl bromide) mal morphinan and isomorphinan will be hereinafter desin a basic medium such as a basic organic solvent (e.g. igllated as morphinan and morphinan pyridine, picoline, dimethylaniline, diethylamine, triethylrespectively- The Position-numbering hereinafter amine), a mixture of the said basic organic solvent with ployed for the morphinan derivatives is that generally aca neutral Organic l t etone, dioxane, rtetrahycepted in morphinan chemistry as shown in the above plane formula.

The objective unsaturated morphinan derivatives in the present invention are representable by the following plane formula:

drofuran, ether) and a combination of an inorganic base (e.g. potassium carbonate, sodium carbonate) with the said neutral organic solvent, usually while heating with reflux. The subsequent deacidation is effected by treating the thus-produced sulfonyloxymorphinan (III) with (I) an organic base (e.g. pyridine, picoline, lutidine, collidine) while heating with reflux.

The objective unsaturated morphinans (I) occur in optically active form as well as in racemic mixture and these are all within the scope of the present invention.

The unsaturated morphinans (1) form acid addition salts with organic and inorganic acids. Illustrative acid addition salts include the hydrohalide (e.g. hydrochloride, wherein R represents a lower alkyl group (e-gmethyl, hydrobromide, hydroiodide), sulfate, phosphate, nitrate, ethyl propyl) R represents a hydrogen atom an aryloxy tartrate, salicylate, benzoate, malate, citrate, acetate, etc. group phenyloxy nelphthyloxy) or a Substituted The thus-produced unsaturated morphinans (I) and aryloxy group substituted phenyloxy Subsmuted acid addition salts thereof are useful as anti-tussive, anallllfeliglllylggl l u e r a l l oi y iigl fi g ggfs fj gesic, narcotic, anti-extensor and/0r anti-electroshockoxy, piopoxy), nitro or amino, R" represents a lower convulsrfmt agents alkyl group methyl, ethyl, propyl), X represents Practical and presently preferred embodiments of the a h d atom, a h d l group an acyloxy group present mvention are illustrated by the following ex- Such as lower alkanoyloxy (e,g. acetyloxy, propionyloxy, amples. In the examples, abbreviations each have conbutylyloxy) and wherein a double bond is present in the ventional meanings, e.g. mg.=milligram(s), g.=gram(s), C-ring, and show various pharmacological activities such 7 ml=milli1itre(s), C.=degrees centigrade.

3 4 EXAMPLE 1 The methiodide: M.P., 207 to 208 C. Preparation of a mixture of (-)-3-methoxy-N-methyl-A The starting material of this example, ()-3-methoxymorphinan (cis) and ()-3-meth0xy-N-methyl-A 6a-hydroxy-N-methylmorphinan (cis), is prepared from morphinan (cis) an It so 0-" A mixture of ()-3-methoxy-6tx-hydroxy-N-methyl desoxydihydrothebainone [Sawa et al.: Tetrahedron, vol. morphinan (cis) (2.0 g.) and p-toluenesulfonyl chloride 15, p. 154 (1961)] according to the following scheme:

Reduction with L h zeep aiie liqCH;

(3.5 g.) in pyridine (23.2 ml.) is heated on a steam bath EXAMPLE 2 for 3 hours. After removal of the pyridine under reduced Preparation of a mixture f 3 ;h 1v ;h l pressure, the resulting product is made to alkalinity with A -m0rphinan (cis) and (-)-3 h -N. h l.

ammonia-water and shaken with ether. The ether layer is 09 A -morphinan (cis) oncusoo evaporate-d to give crude ()-3-methoxy-6a-p-toluenesul- A mixture of (-)-3-meth0xy-6,6-hydr0xy-N-methylfonyl-N-methylmorphinan (cis) (2.4 g.). morphinan (cis) (1.4 g.) and p-toluenesulfonyl chloride A mixture of Crude Y- 'P- (2.5 g.) in pyridine (17 ml.) is heated on a steam bath fonyl-N-Inet'hylmofphinan above p for 3 hours. The reaction mixture is treated as in Expared with collidine (25.5 ml.) is refluxed for 2.5 hours. ample 1 whereby there is obtained crude )-3 h After cooling, ether (50 ml.) is added to the react1on 6B p toluenesulfonyloxy N methylmorphinan (cis) mixture, washed with 10% sodium carbonate and the (26 as an oiL ether evaporated. The resultant is subjected to steam distillation to remove the collidine. The residue is dissolved in 1% hydrochloric acid, washed with benzene, made to alkalinity with sodium carbonate and shaken with chl0ro form. The chloroform layer is evaporated. The residue is dissolved in benzene and chromatographed on alumina 1S obtamed a mlxture of Y' 3 to eliminate impurities. The resulting benzene solution is morphlllan and Y' y evaporated and crystallized from petroleum ether to give Phinan as Crystals melting at 80 to A mixture of crude ()-3-methoxy-6B-p-toluenesulfonyl-N-methylmorphinan (cis) (2.6 g.) above prepared with collidine (27 ml.) is refluxed for 2.5 hours. The reaction mixture is treated as in Example 1 whereby there a mixture of (-)-3-methoxy-N-methyl-A -morphinan The starting material of this example, )-3-methoxy- (cis) and (--)-3-n1ethoxy-N-methyl-A -morphinan (cis) 6/i-hydroxy-N-methylmorphinan (cis), is prepared from (1.4 g.) as crystals melting at 80 to 82 C. desoxydihydrothebainone [Sawa et al.: Tetrahedron, vol.

y for is zs 15, p. 154 (1961)] according to the following scheme: 5.20. Found: C, 80.35; H, 8.73; N, 5.51.

(EHO

Reduction with sodium boroh dride 3 Ii -61% EXAMPLE 3 Preparation of a mixture of (-)-3-methoxy-4-phenyl0xy- N-methyl-Aimorphinan (cis) and ()-3-meth0xy-4- ph enyloxy-N-methyl-n -morphinan (cis) To a solution of (+)-3-methoxy-4-phenyloxy-6ot-hydroxy-N-methylmorphinan (cis) (3.8 g.) in pyridine (11.5 ml.), there is added a solution of p-toluenesulfonyl chloride (2.8 g.) in pyridine (8.5 ml.), and the resultant mixture is allowed to stand at room temperature to C.) for 21 hours. The reaction mixture is poured onto ice-water, made to alkalinity with ammonia-water and shaken with benzene. Thev benzene layer is Washed with Water ml.) and evaporated. The residue is combined With ethanol (30 m1.) and distilled to remove the pyridine. The resultant is dissolved in acetone and treated with oxalic acid to give (-|-)-3-methoXy-4-phenyloxy 6a-p-toluenesulfonyloxy-N-methylrnorphiuan (cis) oxalate (4.9 g.) as a solid melting at 158 to 159 C.

The )-3-methoxy-4-phenyloxy-fioz-p-toluenesulfonyloxy-N-methylmorphinan (cis) (3.7 g.) obtained by treating the above prepared oxalate (4.5 g.) with aqueous Treatment; with h droohloric acid.

product (2.6 g.) is dissolved in ether and chromatographed on alumina (15 g.) to eliminate impurities. The ether solution is evaporated and crystallized from methanol to give a mixture of (-)-3-methoxy-4-phenyloxy- N-methyl-A morphinan (cis) and (-)-3-methoxy-4- phenyloxy-N-methyl-A -morphinan (cis) (2.5 g.). When recrystallized from methanol, there are firstly obtained the crystals melting at 81 to 83 C. (decomp.) and showing 16.7 (ethanol) and secondly the crystals melting at 87 to 89 C. (moistened at C.) and showing 0.5 (ethanol).

The starting material of this example, (+)-3-methoxy- 4-phenyloxy-6a-hydroxy-N-methylmorphinan (cis), is prepared from -3,6-dimethoxy-4-phenyloxy-N-methyl-A -rnorphinan (cis) [Sawa et al.: Tetrahedron, vol. 15, p. 154 (1961)] according to the following scheme:

Reduction using palladiumestrontium 5 Reduction with sodium boroh dride 3,286,851 7 8 EXAMPLE 4 give a mixture of ()-3-methoxy-4-phenyloxy-N-methyl- A -morphinan (cis) and (--)-3-methoxy-4-pheny1oxy-N- methyl-A -morphinan (cis) (2.8 g.) as crystals melting at 87 to 89 C. (moistened at 80 0.).

Preparation of a mixture of (-)-3-meth0xy-4-phenyl0xy- N -methylA -m0rphinan (cis) and -3-meZhoxy-4- phenyloxy-N-methyl-A -morphinan (cis) To a solution of (+)-3-methoxy-4-phenyloxy-6fl-hy- The starting material of this example, (+)-3-methoxydroxy-N-methylmorphinan (cis) (7.6 g.) in pyridine (32 4-phenyloxy-6 3-hydroxy--methylmorphinan (cis), is prern1.), there is added a solution of p-toluenesulfonyl chopared from (+)-3-methoxy-4-phenyloxy-6-oxo-N-methylride (5.7 g.) in pyridine (32 ml), and the resultant mixmorphinan (cis) [cf. Example 3 of this specification] acture is allowed to stand at room temperature (15 to cording to the following scheme:

0 H G H O 6 5 6 5 aeauatim with I sodium borohzdrideg it-cH 3 0 H0 C.) for 14 hours. The reaction mixture is poured onto EXAMPLE 5 ice-water and made to alkalinity with ammonia-Water.

The precipitate is collected by filtration and washed with Pr paration of a mixture of (+)-3-methoxy-4-phenyloxywater to give crude (+)-3-methoxy-4-pheny1oxy-6,6-p- N-methyl-M-morphinan (cis) and (+)-3-meth0xy-4- toluenesulfonyloxy-N-methylmorphinan (cis) (8.5 g.) as pherzyloxy-N-methyl-A' -morphimm (cis) crystals melting at 174 to 175 C. The filtrate is con- To a solution of (+)-3-methoxy-4-phenyloxy-7ot-hydensed in vacuo, mixed with Water and made to alkalinity droxy-N-methylmorphinan (cis) (2.0 g.) in pyridine (10 With amm0nia-W t n The pre ipi e i ollec d y filml.), there is added a solution of p-tolenesulfonyl chloride tration and Washed with water to give the additional crude (1.5 g.) in pyridine (6 ml.), and the res l ant miXtUIc i8 Crystals 2-) 0f the Same cOITIPOUIId- The crude Y allowed to stand at room temperature (15 to 30 C.) for tals are combined together and recrystallized from ethanol 12 hours The reaction mixture is treated as in Example to give the pure crystals (8.0 g.) melting at 183 to 184 4 whereby 3 methoxy 4 phenyloxy 7wPtoluenesuL i iggfi +1750 (ch1orfrm)' [M13265 +5280 fonyloXy-N-methylmorphinan (cis) (2.1 g.) is obtained. A solution of (+)-3-methoxy-4-phenyloxy-7a-p-tol- ZZ 'ZET F for g g' uene-sulfonyloxy-N-methylmorphinan (cis) (2.1 g.) oun above prepared in collidine (20 ml.) is refluxed for 2.5

hours. The reaction mixture is treated as 111 Example A solution of (+)-3-methoxy-4-phenyloxy-6,8-p-toluenesulfonyloxy-N-methylirnorphinan (cis) (4.0 g.) pre- 4 wherebysa mlxtfll'e of Y' 'P Y 3 pared above in collidine (40 ml.) is refluxed for 25 hours. N'methyl'A 'morphlnan (C15) and After cooling, the reaction mixture is combined with ether P Y Y- y 8-) (50 ml), washed with 10% sodium carbonate and the soltamed Crystals melting at 95 t0 (m i Hed at vent removed by distillation and steam distillation. The 84 C.) (crystallized from methanol). [M +158: residue is dissolved in ether and chromatographed on alu- 2 (ethanol).

mina (15 g.) to eliminate impurities. The resultant ether The starting material of this example, (+)-3-methoxy solution is evaporated and crystallized from methanol to 4-phenyloxy-7ot-hydroxy-N-methylmorphinan (cis), is

prepared from sinomenine 4-phenyl ether [Sawa et al.: Tetrahedron, vol. 15, p. 144 (1961)] according to the following scheme:

C H O Reduction according to \dolff-Kishner method, a

acting -3-methoxy-4-phenyloxy-Got-p-toluenesulfonyloxy-N-methylmorphinan (cis) in admixture with collidine under reflux.

c 3 0 Treatment with Reduction with hydrochloric acid sodium borohydride. a

What is claimed is:

1. 3 methoxy-4-phenyloxy-6a-p toluenesulfonyloxy-N-methylmorphinan (cis).

2. 3 methoxy 4 phenyloxy-6fl-p-toluenesulfonyloxy-N-methylmorphinan (cis).

3. 3 methoxy 4 phenyl0xy-7a-p-to1uenesulfonyloxy-N-methylmorphinan (cis).

4. A mixture of (a) a compound of the plane formula:

lower alkyl-O N-lower alkyl r wherein R is a member selected from the group con- 50 sisting of phenyloxy, lower alkylphenyloxy, lower alkoxyphenyloxy, nitrophenyloxy and aminophenyloxy and (b) a compound of the plane formula:

lower alkyl-O N-lower alkyl wherein R has the precedingly-recited same significance, prepared by reacting 3-lower alkoxy-4-R-6-sulfonyloxy- N-lower alkylmorphinan in admixture with organic base under reflux, R having the aforesaid significance.

5. A mixture of 3 methoxy 4-phenyloxy-N- methyl A morphinan (cis) and 3-meth0xy-4- phenyloxy-N-methyl-A -morphinan (cis), prepared by re- 6. A mixture of (a) a compound of the plane formula:

lower alkyl- 0 N-lower alkyl wherein R is a member selected from the group consisting of phenyloxy, lower alkylphenyloxy, lower alkoxyphenyloxy, nitrophenyloxy and aminophenyloxy, and (b) a compound of the plane formula:

lower alkyl-o N-lower alkyl 8. A compound of the formula:

lower alkyl-O lower allay].

R" SO20...

lower alkyl-O -10Wer alkyl R" SO wherein R is a member selected from the group consisting of phenyloxy, lower alkylphenyloxy, lower alkoxyphenyloxy, nitrophenyloxy and aminophenyloxy, and R' is a member selected from the group consisting of lowerkalkyl, phenyl, lower alkylphenyl and phenyl(lower)- a1 yl.

10. A compound of the formula:

lower alkyl-IO.

N-Iowar 'alk l wherein R is a member selected from the group consisting of phenyloxy, lower alkylphenyloxy, lower alkoxyphenyloxy, nitrophenyloxy and aminophenyloxy, and R is a member selected from the group consisting of lower alkyl, phenyl, lower alkylphenyl and phenyl(lower)a1kyl.

References Cited by the Examiner UNITED STATES PATENTS 4/1963 SaWa. et al. 260-285 OTHER REFERENCES Gates et al., J. Am. Chem. Soc., vol. 78, pp. 1380- 1393 (1956).

Gates et al., I. Am. Chem. Soc., vol. 80, pp. 1186- 1194 (1958).

Hartung, Industrial and Engeering Chemistry, vol. 37, pages 126-127 (1945).

NICHOLAS S. RIZZO, Primary Examiner.

IRVING MARCUS, Examiner. 

1. +()-3-METHOXY-4-PHENYLOXY-6A-P-TOLUENESULFONYLOXY-N-METHYLMORPHINAN (CIS).
 9. A COMPOUND OF THE FORMULA: 